Angiogenesis (or neovascularization), the development of blood vessels, plays an important role in embryonic development, in the inflammatory response, in the development of metastases (tumor induced angiogenesis or TIA), in diabetic retinopathy, in the formation of the arthritic panus and possibly in psoriasis. In tumor angiogenesis, for example, capillary sprouts are formed, their formation being induced by a group of tumor cells. These sprouts eventually develop into a microcirculatory network within the tumor mass. There are two principle types of tumor angiogenesis in terms of the events which follow implantations of metastatic seedlings on surfaces and in organs.
The first or primary angiogenesis is the initial vascularization of the mass of multiplying tumor cells and is regarded as an essential prerequisite for the survival and further growth of a metastatic deposit.
The second is a continuing or secondary angiogenesis and is the phenomenon which occurs in waves at the periphery of a growing tumor mass. This second angiogenesis is essential for the accretion of new microcirculatory territories into the service of the expanding and infiltrating tumor.
Auerbach, Lymphokines, 4, 69 (1981) reviews angiogenesis inducing factors. Judah Folkman, one of the pioneers in this field reviews tumor angiogenesis in Ann. Int. Med, 82 96 (1975) and discussed evidence for the existence of a diffusible tumor angiogenesis factor (TAF).
Several naturally-occurring angiogenesis inhibitors have been found. Research Resources Reporter, page 7, December, 1981 reports the isolation of a factor from cartilege which slows tumor growth and also reports similar factors from other tissues. These factors (AI) all seems to be proteins of 3,500 to 25,000 daltons. Other diseases to be treated with AI include arthritis, diabetic or sickle-cell retinopathy and psoriasis. Science 216, 1304 (1982) reported the characterization of a specific AI protamine by Folkman and Taylor [(see also Nature, 297, 307(1982)] which factor inhibited lung metastases and B16 melanoma in mice. Simple, small molecular weight chemical AI's were not known as of Jan. 1, 1982.
Methyl ethers of ascorbic acid were synthesized by Haworth and coworkers during the classical elucidation of the structure of ascorbic acid-vitamin C. The 3-methyl, 2,3-dimethyl and 2,3,5,6-tetramethyl ethers are described (see J. Chem. Soc., 1934, 1556). Diazomethane was used as the methylating agent. Herbert et al. J. Chem. Soc., 1933 1270 also prepared the mono, di and tetramethyl ethers of ascorbic acid, using dimethyl sulfate and base (50% aqueous KOH) for the monoether, diazomethane for the diether and silver oxide plus MeI for the tetramethyl ether from the dimethyl ether.
Reichstein et al., Helv. Chim. Acta, 17, 510 (1934) also prepared the 3-methyl ether of ascorbic acid using diazomethane, and then prepared a ketal therefrom with acetone.
Vestling and Rebstock, J. Biol. Chem, 164, 631 (1946) investigated the antiscorbutic activity of 3-methylascorbic acid (prepared via diazomethane) by intraperitoneal injection of an ascorbic acid solution in distilled water into scorbutic guinea pigs. Bezssonoff and Sacrez, C. R. Soc. Biol, 124, 356 (1937) earlier had found that 2,3-dimethylascorbic acid was devoid of Vitamin C activity but that the 3-methyl ether was active. The compounds were administered orally in aqueous solution. Gould et al., Arch. Biochem, 23, 205 (1949) verified the fact that 3-methylascorbic acid had about 1/50 the vitamin C activity of ascorbic acid. For test purposes, the compound was added to the diet of scorbutic guinea pigs. Shrihatti et al, Indian J. Chem., 15B, 861 (1977) attempted to resolve the divergent reports on the vitamin C activity of the 3-methyl ether of ascorbic acid and developed an unambiguous procedure for preparing that compound and also the 2,3-dimethyl ether. Diazomethane was the methylating agent.
Rokosova and Chvapil, Connective Tissue Res., 2, 215 (1974) tested 3-methyl-L-ascorbic acid for its ability to stimulate proline hydroxylation in scorbutic granulomas. The compound had an effect in vitro but was not tested in vivo.
Radford et al J. Org. Chem., 44, 658 (1979) published a carbon-13 nmr of 3-methylascorbic acid, among other compounds, and confirmed the previously assigned structure.
Parish and Gilliom, Carbo. Res., 102, 302 (1982) prepared 3-O-(3,3-dimethyl-2-oxobutyl)ascorbate, (3-t-butyloxymethyl-L-ascorbic acid).
U.S. Pat. No. 4,111,958 prepared ascorbic acid from gulono-14-lactone, galactano-1,4-lactone, iodono-1,4-ketone or talono-14-lactone by protecting, C-2 or C-3 position of the sugar lactone, as by ether formation, and oxidizing the remaining C-2 or C-3 free hydroxyl to yield an ether of ascorbic acid (L or D). The usual ether protecting group was a 3,5 ketal. The oxidized product is thus a 3,5-ketal of ascorbic acid.
Other methylated hexose lactones have been prepared:
2,3,6-tri-O-methyl-D-galactano-1,4-lactone--Lew and Heidelberger, Carb. Res, 52, 255 (1976)
2,3,5-tri, 2,3,5,6-tetra and 3,5-di-O-methyl-D-mannofuranose, Siddiqui and Murty Carb. Res, 8, 477 (1968)
3,5,6-tri-O-methyl-D-mannono-1,4-lactone--Saddiqui, Carb. Res, 9, 344 (1969).
The 3-benzylether of ascorbic acid is reported by Jackson and Jones in Can. J. Chem. 43, 450 (1965) as well as the 2,3-dibenzylether and the corresponding-5,6-O-isopropylidene derivatives.
U.S. Pat. No. 4,153,613 discloses the 5,6-O-dodecanal, hexadecanal, tetradecanal and octadecanal acetals of L-ascorbic acid as well as shorter chain acetals. Ketals are also described. The compounds are used to prevent nitrosamine formation in bacon.
Jung and Shaw, J. Am. Chem. Soc., 102, 6304 (1980) utilized the 5,6-acetonide of ascorbic acid or the 2,3-dimethylether of ascorbic acid as a chiral starting material for preparing (R)-glycerolacetonide. Diazomethane was used to prepare the dimethyl ether.
U.S. Pat. No. 4,208,434 discloses the use of C-2 and/or C-3 C.sub.1-10 alkyl ethers of ascorbic acid and 5,6-ketals thereof, as stabilizers of certain natural anthocyanin pigments to be added to soft drinks.
To summarize, lower alkyl ethers of ascorbic acid and its ketals are known as is the benzyl ether.